EP1541569B1 - Process for producing n-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine and intermediate - Google Patents

Process for producing n-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine and intermediate Download PDF

Info

Publication number
EP1541569B1
EP1541569B1 EP03741391A EP03741391A EP1541569B1 EP 1541569 B1 EP1541569 B1 EP 1541569B1 EP 03741391 A EP03741391 A EP 03741391A EP 03741391 A EP03741391 A EP 03741391A EP 1541569 B1 EP1541569 B1 EP 1541569B1
Authority
EP
European Patent Office
Prior art keywords
thienyl
monoalkyl
oxo
propenamine
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP03741391A
Other languages
German (de)
French (fr)
Other versions
EP1541569A1 (en
EP1541569A4 (en
Inventor
K. Fine Chem. Res. Lab. Sumitomo Seika KOGAMI
N. Fine Chem. Res. Lab. Sumitomo lab. HAYASHIZAKA
S. Fine Chem. Res. Lab. Sumitoma Seika SATAKE
I. Sumitomo Seika Chemicals Co. LTD FUSEYA
H. Sumitomo Seika Chemicals Co. Ltd. KAGANO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sumitomo Seika Chemicals Co Ltd
Original Assignee
Sumitomo Seika Chemicals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Seika Chemicals Co Ltd filed Critical Sumitomo Seika Chemicals Co Ltd
Publication of EP1541569A1 publication Critical patent/EP1541569A1/en
Publication of EP1541569A4 publication Critical patent/EP1541569A4/en
Application granted granted Critical
Publication of EP1541569B1 publication Critical patent/EP1541569B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention relates to a process for producing an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine.
  • N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamines are highly reactive and useful as intermediates for various pharmaceuticals.
  • the present invention relates also to a novel compound for use as a production intermediate of an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine, i.e., a ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine, and a production process thereof.
  • An example of a method known for producing an N- monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is reducing 1-(2-thienyl)-3-chloropropane-1-one with sodium borohydride in ethanol to give 3-chloro-1-(2-thienyl)-1-propanol, halogen-exchanging this 3-chloro-1-(2-thienyl)-1-propanol with sodium iodide in acetone to give 3-iodo-1-(2-thienyl)-1-propanol, and reacting this 3-iodo-1-(2-thienyl)-1-propanol with an aqueous monomethylamine solution in tetrahydrofuran ( CHIRALITY, 12, 26-29 (2000 )).
  • This method is not industrially advantageous since the starting material, i.e., 1-(2-thienyl)-3-chloropropane-1-one, is a highly unstable compound.
  • An example of a method known for producing N,N -dimethyl-3-hydroxy-3-(2-thienyl)propanamine is reacting 2-acetylthiophene with a dimethylamine hydrochloride in isopropanol in the presence of paraformaldehyde and hydrochloric acid to give 2-thienyl 2-dimethylaminoethyl ketone, and reducing this ketone with sodium borohydride in ethanol (Japanese Unexamined Patent Publication No. 1995-188065 ).
  • N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is produced according to the method described immediately above using a monoalkylamine hydrochloride in place of a dimethylamine hydrochloride, it is problematic in that a dimeric N , N' , N "-alkyl-bis[1-[3-oxo-3-(2-thienyl)propane]] amine is generated due to the unstable production intermediate, i.e., 2-thienyl 2-monoalkylaminoethyl ketone, which results in a low yield of N -monalkyl-3-hydroxy-3-(2-thienyl)propanamine obtained after the reduction with sodium borohydride.
  • EP-A-0650965 describes process for producing N -methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine comprising the step of reducing 2-thienyl-2-dimethylaminoethyl ketone.
  • An object of the present invention is to provide a process for producing an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine in an industrially inexpensive and easy manner, and a production intermediate thereof.
  • the inventors conducted extensive research to attain the objectives described above and found that a novel compound, i.e., a ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine, is useful as a starting material for producing an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine.
  • the present invention provides processes for producing an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine, a production intermediate of this compound, i.e., a ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine, and production processes thereof as described below:
  • the method for producing an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine comprises the step of reducing a ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by General Formula (1): wherein R is C 1-4 alkyl.
  • C 1-4 alkyl examples are methyl, ethyl, n- propyl, isopropyl, n -butyl, t -butyl, etc.
  • reducing agents usable for the reduction are diisobutylaluminum hydride and like metal hydrides; sodium borohydride, sodium cyanoborohydride, lithium borohydride, potassium borohydride, and like complex metal hydrides; borane, 9-borabicyclo[3,3,1]nonane, and like borane compounds; hydrogen; etc.
  • complex metal hydrides are preferable because of their high reducing power, with sodium borohydride and sodium cyanoborohydride being particularly preferable.
  • the amount of reducing agent is preferably 0.1 to 7 mol, and more preferably 0.2 to 5 mol, per mol of ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine. Amounts of reducing agent less than 0.1 molar equivalents are likely to result in an impaired yield because the reaction does not proceed sufficiently. On the other hand, amounts of reducing agent exceeding 7 mol do not exert effects justifiable for such amounts, and are therefore not economical.
  • reaction solvents usable in the reduction of the ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine are pentane, hexane, cyclohexane, heptane, and like aliphatic hydrocarbons; benzene, toluene, xylene, chlorobenzene, and like aromatic hydrocarbons; diethyl ether, tetrahydrofuran, dioxane, and like ethers; methanol, ethanol, and like alcohols; methyl acetate, ethyl acetate, butyl acetate, and like esters; etc.
  • aromatic hydrocarbons are preferable, and toluene is particularly preferable.
  • the amount of reaction solvent is preferably 0.1 to 30 times, and more preferably 0.5 to 20 times, the weight of ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine. Amounts of reaction solvent less than 0.1 times are likely to make stirring difficult. On the other hand, amounts of reaction solvent exceeding 30 times are likely to impair volume efficiency.
  • the reduction of the ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine is preferably carried out in the presence of a proton-donating compound for the reduction reaction to proceed efficiently.
  • proton-donating compounds are methanol, ethanol, and like alcohols; formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, and like carboxylic acids; hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, and like hydrogen halides; sulfuric acid; methylsulfuric acid, p- toluenesulfonic acid, and like sulfonic acids; etc.
  • carboxylic acids are preferable, and acetic acid is particularly preferable, for the reduction reaction to readily progress.
  • the amount of proton-donating compound is preferably 20 mol or less, and more preferably 0.1 to 10 mol, per mol of ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine. Amounts of proton-donating compound exceeding 20 molar equivalents do not exert effects justifiable for such amounts, and are therefore not economical.
  • the temperature for reducing the ( Z )- N- monoalkyl-3-oxo-3-(2-thienyl)propenamine is preferably from 0°C to 150°C, and more preferably from 20°C to 100°C. Temperatures lower than 0°C are likely to slow the reaction rate, thereby prolonging the reaction. On the other hand, temperatures exceeding 150°C may result in impurity generation.
  • the reaction time varies depending on the reaction temperature, it is preferably from 1 to 30 hours.
  • the reaction solution containing the N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is phase-separated by adding water when a water-immiscible solvent is used as a reaction solvent.
  • a water-miscible solvent is used as a reaction solvent
  • water and a water-immiscible solvent e.g., toluene
  • the solvent contained in the organic phase obtained by the phase separation is distilled off, and crystals thus precipitated are then recrystallized, thereby enabling the N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine to be isolated.
  • N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine thus obtained is a compound represented by General Formula (2): wherein R is C 1-4 alkyl.
  • C 1-4 alkyl examples are methyl, ethyl, n- propyl, isopropyl, n -butyl, t -butyl, etc.
  • N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamines are N -monomethyl-3-hydroxy-3-(2-thienyl)propanamine, N -monoethyl-3-hydroxy-3-(2-thienyl)propanamine, N -mono( n -propyl)-3-hydroxy-3-(2-thienyl)propanamine, N -monoisopropyl-3-hydroxy-3-(2-thienyl)propanamine, N -mono( n -butyl)-3-hydroxy-3-(2-thienyl)propanamine, N -mono( t -butyl)-3-hydroxy-3-(2-thienyl)propanamine, etc.
  • N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamines are highly reactive and useful as intermediates for various pharmaceuticals.
  • C 1-4 alkyl examples are methyl, ethyl, n- propyl, isopropyl, n -butyl, t -butyl, etc.
  • ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamines are ( Z )- N -monomethyl-3-oxo-3-(2-thienyl)propenamine, ( Z )- N -monoethyl-3-oxo-3-(2-thienyl)propenamine, ( Z )- N -mono( n -propyl)-3-oxo-3-(2-thienyl)propenamine, ( Z )- N -monoisopropyl-3-oxo-3-(2-thienyl)propenamine, ( Z )- N -mono( n -butyl)-3-oxo-3-(2-thienyl)propenamine, ( Z )- N -mono( t -butyl)-3-oxo-3-(2-thienyl)propenamine, etc.
  • ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamines represented by General Formula (1) can be obtained by reacting an alkali metal salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal represented by General Formula (3): wherein M is an alkali metal atom, with a monoalkylamine compound represented by General Formula (4): H 2 N-R (4) wherein R is C 1-4 alkyl.
  • Alkali metal salts of ⁇ -oxo- ⁇ -(2-thienyl)propanal usable in the present invention are compounds represented by General Formula (3): wherein M is an alkali metal atom.
  • alkali metal atoms examples include lithium, sodium, potassium, etc.
  • alkali metal salts of ⁇ -oxo- ⁇ -(2-thienyl)propanal are the lithium salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal, the sodium salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal, the potassium salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal, etc.
  • the sodium salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal is preferable.
  • Methods for producing alkali metal salts of ⁇ -oxo- ⁇ -(2-thienyl)propanal usable in the present invention are not limited.
  • An example thereof is to react 2-acetylthiophene with an alkali metal methoxide in ethyl formate (Japanese Unexamined Patent Publication No. 1990-202865 ).
  • Monoalkylamine compounds usable herein are compounds represented by General Formula (4): H 2 N-R (4) wherein R is C 1-4 alkyl.
  • C 1-4 alkyl examples are methyl, ethyl, n- propyl, isopropyl, n -butyl, t -butyl, etc.
  • monoalkylamine compounds are monomethylamine, monoethylamine, mono( n -propyl)amine, monoisopropylamine, mono( n -butyl)amine, mono( t -butyl)amine, etc.
  • monomethylamine is preferable.
  • Hydrochloric acid salts and sulfuric acid salts of the aforementioned monoalkylamine compounds can be used as monoalkylamine compounds in the present invention.
  • the amount of monoalkylamine compound is preferably 1 to 5 mol, and more preferably 1 to 3 mol, per mol of alkali metal salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal. Amounts of monoalkylamine compound less than 1 mol are likely to result in an impaired yield. On the other hand, amounts of monoalkylamine compound exceeding 5 mol do not exert effects justifiable for such amounts, and are therefore not economical.
  • reaction solvents usable in the reaction of the alkali metal salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal and the monoalkylamine compound are pentane, hexane, cyclohexane, heptane, and like aliphatic hydrocarbons; benzene, toluene, xylene, chlorobenzene, and like aromatic hydrocarbons; diethyl ether, tetrahydrofuran, dioxane, and like ethers; methanol, ethanol, and like alcohols; methyl acetate, ethyl acetate, butyl acetate, and like esters; etc.
  • alcohols are preferable, and methanol is particularly preferable.
  • the amount of reaction solvent is preferably 0.1 to 30 times, and more preferably 0.5 to 20 times, the weight of alkali metal salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal. Amounts of reaction solvent less than 0.1 times are likely to make stirring difficult whereas amounts of reaction solvent exceeding 30 times are likely to impair volume efficiency.
  • the temperature for the reaction of the alkali metal salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal with the monoalkylamine compound is preferably from 0°C to 100°C, and more preferably from 10°C to 80°C. Reaction temperatures lower than 0°C are likely to slow the reaction rate, thereby prolonging the reaction. On the other hand, reaction temperatures exceeding 100°C are likely to result in impurity generation.
  • the reaction time varies depending on the reaction temperature, it is preferably from 1 to 30 hours.
  • the solvent is distilled off, and an aqueous sodium hydroxide solution and an organic solvent such as methyl t -butyl ether, toluene, or the like are added to the reaction solution for phase separation to obtain an organic phase.
  • the solvent is distilled off from the thus-obtained organic phase, and the thus-precipitated crystals are washed and dried, thereby enabling the ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine to be isolated.
  • an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine can be obtained without isolating the ( Z )- N -monoalkyl-3-oxo-3-(2-thienyl)propenamine above by subjecting it to reduction.
  • the present invention provides a process for producing an N -monoalkyl-3-hydroxy-3-(2-thienyl)propanamine in an industrially inexpensive and easy manner, which is highly reactive and useful as an intermediate for various pharmaceuticals, and a production intermediate thereof.
  • reaction solution was cooled to 25°C, and 30 g of a 12.5 wt.% aqueous sodium hydroxide solution was added thereto for phase separation.
  • the solvent was distilled off from the organic phase thus separated, and the thus-precipitated crystals were filtered.
  • the yield thereof based on ( Z )- N -monomethyl-3-oxo-3-(2-thienyl)propenamine was 75.0%.
  • reaction solution was cooled to 25°C, and 290 g of a 12.5 wt.% aqueous sodium hydroxide solution was added thereto for phase separation.
  • the solvent was distilled off from the organic phase thus separated, and the thus-precipitated crystals were filtered.
  • the yield thereof based on the sodium salt of ⁇ -oxo- ⁇ -(2-thienyl)propanal was 72.0%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine represented by the general formula (2): (2) (wherein R represents C1-4 alkyl), characterized by reducing a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by the general formula (1): (1) (wherein R is the same as the above). By the process, an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine useful as an intermediate for various medicines can be industrially and easily produced at low cost.

Description

    TECHNICAL FIELD
  • The present invention relates to a process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine. N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamines are highly reactive and useful as intermediates for various pharmaceuticals. The present invention relates also to a novel compound for use as a production intermediate of an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine, i.e., a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine, and a production process thereof.
    • BACKGROUND ART
  • An example of a method known for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is reducing 1-(2-thienyl)-3-chloropropane-1-one with sodium borohydride in ethanol to give 3-chloro-1-(2-thienyl)-1-propanol, halogen-exchanging this 3-chloro-1-(2-thienyl)-1-propanol with sodium iodide in acetone to give 3-iodo-1-(2-thienyl)-1-propanol, and reacting this 3-iodo-1-(2-thienyl)-1-propanol with an aqueous monomethylamine solution in tetrahydrofuran (CHIRALITY, 12, 26-29 (2000)). This method is not industrially advantageous since the starting material, i.e., 1-(2-thienyl)-3-chloropropane-1-one, is a highly unstable compound.
  • An example of a method known for producing N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine is reacting 2-acetylthiophene with a dimethylamine hydrochloride in isopropanol in the presence of paraformaldehyde and hydrochloric acid to give 2-thienyl 2-dimethylaminoethyl ketone, and reducing this ketone with sodium borohydride in ethanol (Japanese Unexamined Patent Publication No. 1995-188065 ).
  • When an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is produced according to the method described immediately above using a monoalkylamine hydrochloride in place of a dimethylamine hydrochloride, it is problematic in that a dimeric N, N', N"-alkyl-bis[1-[3-oxo-3-(2-thienyl)propane]] amine is generated due to the unstable production intermediate, i.e., 2-thienyl 2-monoalkylaminoethyl ketone, which results in a low yield of N-monalkyl-3-hydroxy-3-(2-thienyl)propanamine obtained after the reduction with sodium borohydride.
  • EP-A-0650965 describes process for producing N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine comprising the step of reducing 2-thienyl-2-dimethylaminoethyl ketone.
    • DISCLOSURE OF THE INVENTION
  • An object of the present invention is to provide a process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine in an industrially inexpensive and easy manner, and a production intermediate thereof.
  • Other objects and characteristics of the present invention will become evident by the disclosure provided hereinbelow.
  • The inventors conducted extensive research to attain the objectives described above and found that a novel compound, i.e., a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine, is useful as a starting material for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine. They found also that, by reducing this novel compound, an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine can be produced in an industrially inexpensive and easy manner and that this (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine can be produced by reacting an alkali metal salt of β-oxo-β-(2-thienyl)propanal with a monoalkylamine compound. The inventors accomplished the present invention based on these findings.
  • In other words, the present invention provides processes for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine, a production intermediate of this compound, i.e., a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine, and production processes thereof as described below:
    1. 1. A process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine represented by General Formula (2):
      Figure imgb0001
       wherein R is C1-4 alkyl, comprising the step of reducing a-(Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by General Formula (1):
      Figure imgb0002
       wherein R is as defined above.
    2. 2. A (Z)-monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by General Formula (1):
      Figure imgb0003
       wherein R is C1-4 alkyl.
    3. 3. The (Z)-N-monoalkyl-3=oxo-3-(2-thienyl)propenamine according to Item 2, wherein R in General Formula (1) is methyl.
    4. 4. A process for producing a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by General Formula (1):
      Figure imgb0004
       wherein R is C1-4 alkyl, comprising the step of reacting an alkali metal salt of β-oxo-β-(2-thienyl)propahal represented by General Formula (3) :
      Figure imgb0005
       wherein M is an alkali metal atom, with a monoalkylamine: compound represented by General Formula (4):

              H2N-R     (4)

      wherein R is as defined above.
    5. 5. The process according to item 4 which includes a final step of reducing the (Z)-(N)-monoalkyl-3-oxo-3-(2)-thienyl)propenamine to produce an N-monozlkul-3-hydroxy-3-(2-thienyl)propanamihe represented by General Formula (2):
      Figure imgb0006
       wherein R is C1-4 alkyl.
    6. 6. The process according to Item 1 or 5, wherein the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine is reduced using sodium borohydride or sodium cyanoborohydride.
    7. 7. The process according to Item 1, 5 or 6, wherein the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine is reduced in the presence of a proton-donating compound.
  • Hereinbelow, the process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine, the production intermediate of this compound, i.e., a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine, and the production process thereof are described in more detail.
    • [Production of N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine]
  • The method for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine comprises the step of reducing a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by General Formula (1):
    Figure imgb0007
     wherein R is C1-4 alkyl.
  • Examples of C1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.
  • Examples of reducing agents usable for the reduction are diisobutylaluminum hydride and like metal hydrides; sodium borohydride, sodium cyanoborohydride, lithium borohydride, potassium borohydride, and like complex metal hydrides; borane, 9-borabicyclo[3,3,1]nonane, and like borane compounds; hydrogen; etc. Among such reducing agents, complex metal hydrides are preferable because of their high reducing power, with sodium borohydride and sodium cyanoborohydride being particularly preferable.
  • The amount of reducing agent is preferably 0.1 to 7 mol, and more preferably 0.2 to 5 mol, per mol of (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine. Amounts of reducing agent less than 0.1 molar equivalents are likely to result in an impaired yield because the reaction does not proceed sufficiently. On the other hand, amounts of reducing agent exceeding 7 mol do not exert effects justifiable for such amounts, and are therefore not economical.
  • Examples of reaction solvents usable in the reduction of the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine are pentane, hexane, cyclohexane, heptane, and like aliphatic hydrocarbons; benzene, toluene, xylene, chlorobenzene, and like aromatic hydrocarbons; diethyl ether, tetrahydrofuran, dioxane, and like ethers; methanol, ethanol, and like alcohols; methyl acetate, ethyl acetate, butyl acetate, and like esters; etc. Among such reaction solvents, aromatic hydrocarbons are preferable, and toluene is particularly preferable.
  • The amount of reaction solvent is preferably 0.1 to 30 times, and more preferably 0.5 to 20 times, the weight of (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine. Amounts of reaction solvent less than 0.1 times are likely to make stirring difficult. On the other hand, amounts of reaction solvent exceeding 30 times are likely to impair volume efficiency.
  • The reduction of the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine is preferably carried out in the presence of a proton-donating compound for the reduction reaction to proceed efficiently. Examples of proton-donating compounds are methanol, ethanol, and like alcohols; formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, and like carboxylic acids; hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, and like hydrogen halides; sulfuric acid; methylsulfuric acid, p-toluenesulfonic acid, and like sulfonic acids; etc. Among such examples, carboxylic acids are preferable, and acetic acid is particularly preferable, for the reduction reaction to readily progress.
  • The amount of proton-donating compound is preferably 20 mol or less, and more preferably 0.1 to 10 mol, per mol of (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine. Amounts of proton-donating compound exceeding 20 molar equivalents do not exert effects justifiable for such amounts, and are therefore not economical.
  • The temperature for reducing the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine is preferably from 0°C to 150°C, and more preferably from 20°C to 100°C. Temperatures lower than 0°C are likely to slow the reaction rate, thereby prolonging the reaction. On the other hand, temperatures exceeding 150°C may result in impurity generation. Although the reaction time varies depending on the reaction temperature, it is preferably from 1 to 30 hours.
  • After the reaction, the reaction solution containing the N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine is phase-separated by adding water when a water-immiscible solvent is used as a reaction solvent. When a water-miscible solvent is used as a reaction solvent, water and a water-immiscible solvent, e.g., toluene, are added for phase separation. The solvent contained in the organic phase obtained by the phase separation is distilled off, and crystals thus precipitated are then recrystallized, thereby enabling the N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine to be isolated.
  • The N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine thus obtained is a compound represented by General Formula (2):
    Figure imgb0008
     wherein R is C1-4 alkyl.
  • Examples of C1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.
  • Specific examples of N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamines are N-monomethyl-3-hydroxy-3-(2-thienyl)propanamine, N-monoethyl-3-hydroxy-3-(2-thienyl)propanamine, N-mono(n-propyl)-3-hydroxy-3-(2-thienyl)propanamine, N-monoisopropyl-3-hydroxy-3-(2-thienyl)propanamine, N-mono(n-butyl)-3-hydroxy-3-(2-thienyl)propanamine, N-mono(t-butyl)-3-hydroxy-3-(2-thienyl)propanamine, etc.
  • Such N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamines are highly reactive and useful as intermediates for various pharmaceuticals.
  • The (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by General Formula (1):
    Figure imgb0009
     wherein R is C1-4 alkyl, used in the process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine of the invention is a novel compound.
  • Examples of C1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.
  • Specific examples of (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamines are (Z)-N-monomethyl-3-oxo-3-(2-thienyl)propenamine, (Z)-N-monoethyl-3-oxo-3-(2-thienyl)propenamine, (Z)-N-mono(n-propyl)-3-oxo-3-(2-thienyl)propenamine, (Z)-N-monoisopropyl-3-oxo-3-(2-thienyl)propenamine, (Z)-N-mono(n-butyl)-3-oxo-3-(2-thienyl)propenamine, (Z)-N-mono(t-butyl)-3-oxo-3-(2-thienyl)propenamine, etc. Among such examples, (Z)-N-monomethyl-3-oxo-3-(2-thienyl)propenamine is preferable.
    • [Production of (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine]
  • (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamines represented by General Formula (1) can be obtained by reacting an alkali metal salt of β-oxo-β-(2-thienyl)propanal represented by General Formula (3):
    Figure imgb0010
     wherein M is an alkali metal atom, with a monoalkylamine compound represented by General Formula (4):

            H2N-R     (4)

    wherein R is C1-4 alkyl.
  • Alkali metal salts of β-oxo-β-(2-thienyl)propanal usable in the present invention are compounds represented by General Formula (3):
    Figure imgb0011
     wherein M is an alkali metal atom.
  • Examples of alkali metal atoms are lithium, sodium, potassium, etc.
  • Specific examples of alkali metal salts of β-oxo-β-(2-thienyl)propanal are the lithium salt of β-oxo-β-(2-thienyl)propanal, the sodium salt of β-oxo-β-(2-thienyl)propanal, the potassium salt of β-oxo-β-(2-thienyl)propanal, etc. Among such examples, the sodium salt of β-oxo-β-(2-thienyl)propanal is preferable.
  • Methods for producing alkali metal salts of β-oxo-β-(2-thienyl)propanal usable in the present invention are not limited. An example thereof is to react 2-acetylthiophene with an alkali metal methoxide in ethyl formate (Japanese Unexamined Patent Publication No. 1990-202865 ).
  • Monoalkylamine compounds usable herein are compounds represented by General Formula (4):

            H2N-R     (4)

    wherein R is C1-4 alkyl.
  • Examples of C1-4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.
  • Specific examples of monoalkylamine compounds are monomethylamine, monoethylamine, mono(n-propyl)amine, monoisopropylamine, mono(n-butyl)amine, mono(t-butyl)amine, etc. Among such examples, monomethylamine is preferable.
  • Hydrochloric acid salts and sulfuric acid salts of the aforementioned monoalkylamine compounds can be used as monoalkylamine compounds in the present invention.
  • The amount of monoalkylamine compound is preferably 1 to 5 mol, and more preferably 1 to 3 mol, per mol of alkali metal salt of β-oxo-β-(2-thienyl)propanal. Amounts of monoalkylamine compound less than 1 mol are likely to result in an impaired yield. On the other hand, amounts of monoalkylamine compound exceeding 5 mol do not exert effects justifiable for such amounts, and are therefore not economical.
  • Examples of reaction solvents usable in the reaction of the alkali metal salt of β-oxo-β-(2-thienyl)propanal and the monoalkylamine compound are pentane, hexane, cyclohexane, heptane, and like aliphatic hydrocarbons; benzene, toluene, xylene, chlorobenzene, and like aromatic hydrocarbons; diethyl ether, tetrahydrofuran, dioxane, and like ethers; methanol, ethanol, and like alcohols; methyl acetate, ethyl acetate, butyl acetate, and like esters; etc. Among such reaction solvents, alcohols are preferable, and methanol is particularly preferable.
  • The amount of reaction solvent is preferably 0.1 to 30 times, and more preferably 0.5 to 20 times, the weight of alkali metal salt of β-oxo-β-(2-thienyl)propanal. Amounts of reaction solvent less than 0.1 times are likely to make stirring difficult whereas amounts of reaction solvent exceeding 30 times are likely to impair volume efficiency.
  • The temperature for the reaction of the alkali metal salt of β-oxo-β-(2-thienyl)propanal with the monoalkylamine compound is preferably from 0°C to 100°C, and more preferably from 10°C to 80°C. Reaction temperatures lower than 0°C are likely to slow the reaction rate, thereby prolonging the reaction. On the other hand, reaction temperatures exceeding 100°C are likely to result in impurity generation. Although the reaction time varies depending on the reaction temperature, it is preferably from 1 to 30 hours.
  • After the reaction, the solvent is distilled off, and an aqueous sodium hydroxide solution and an organic solvent such as methyl t-butyl ether, toluene, or the like are added to the reaction solution for phase separation to obtain an organic phase. The solvent is distilled off from the thus-obtained organic phase, and the thus-precipitated crystals are washed and dried, thereby enabling the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine to be isolated.
  • Moreover, an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine can be obtained without isolating the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine above by subjecting it to reduction.
  • The present invention provides a process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine in an industrially inexpensive and easy manner, which is highly reactive and useful as an intermediate for various pharmaceuticals, and a production intermediate thereof.
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • Examples are given below to illustrate the invention in more detail, but the scope of the invention is not limited to these examples.
    • Example 1
  • 88.1 g (0.50 mol) of the sodium salt of β-oxo-β-(2-thienyl)propanal and 168 g of methanol were introduced into a 1-liter 4-necked flask equipped with a stirrer, condenser, thermometer and dropping funnel. 87.8 g (0.50 mol) of a 38.5 wt.% aqueous monomethylamine hydrochloride solution was added dropwise at 25°C over 20 minutes. After the dropwise addition, reaction was carried out at 30°C for 5 hours.
  • After the reaction, methanol was distilled off, and 121.4 g of a 3.1 wt.% aqueous sodium hydroxide solution and 100 g of methyl t-butyl ether were added for phase separation. The solvent was distilled off from the organic phase thus separated, and the thus-precipitated crystals were filtered. The crystals thus obtained were washed twice with 100 g of ethanol and dried, thereby giving 62.5 g (0.374 mol) of (Z)-N-monomethyl-3-oxo-3-(2-thienyl)propenamine. The yield thereof based on the sodium salt of β-oxo-β-(2-thienyl)propanal was 74.8%.
  • The (Z)-N-monomethyl-3-oxo-3-(2-thienyl)propenamine thus obtained exhibited the following properties:
    • Molecular weight: 167.23
    • Melting point: 85.3°C to 86.4°C
    • Elemental analysis: C, 57.23%; H, 5.55%; N, 8.38%
    • (theoretical value: C, 57.46%; H, 5.42%; N, 8.37%)
    • Infrared absorption spectrum (KBr, cm-1): 3230, 3079, 3064, 2929, 2904, 2813, 1629, 1552, 1513, 1488, 1427, 1413, 1351, 1290, 1251, 1234, 1176, 1145, 1093, 1060, 1012, 979, 954, 856, 842, 759, 740, 698, 663, 565, 468, 453
    • 1H-NMR spectrum (CDCl3, TMS standard) δ (ppm): 9.90 (b, 1H), 7.54 (dd, 1H), 7.45 (dd, 1H), 7.06 (dd, 1H), 6.85 (dd, 1H), 5.57 (d, 1H), 3.05 (d, 3H)
    Example 2
  • 8.7 g (0.052 mol) of (Z)-N-monomethyl-3-oxo-3-(2-thienyl)propenamine as obtained in Example 1, 6.2 g (0.103 mol) of acetic acid, and 42 g of toluene were introduced into a 300 ml 4-necked flask equipped with a stirrer, condenser, thermometer and dropping funnel, and heated to 50°C. After adding 1.966 g (0.052 mol) of sodium borohydride, reaction was carried out at 80°C for 2 hours.
  • After the reaction, the reaction solution was cooled to 25°C, and 30 g of a 12.5 wt.% aqueous sodium hydroxide solution was added thereto for phase separation. The solvent was distilled off from the organic phase thus separated, and the thus-precipitated crystals were filtered. The crystals thus obtained were recrystallized in a mixed solvent of toluene and heptane (weight ratio = 1:3), thereby giving 6.5 g (0.039 mol) of N-monomethyl-3-hydroxy-3-(2-thienyl)propanamine. The yield thereof based on (Z)-N-monomethyl-3-oxo-3-(2-thienyl)propenamine was 75.0%.
    • Example 3
  • 88.1 g (0.50 mol) of the sodium salt of β-oxo-β-(2-thienyl)propanal and 168 g of methanol were introduced into a 1-liter 4-necked flask equipped with a stirrer, condenser, thermometer and dropping funnel. 87.8 g (0.50 mol) of a 38.5 wt.% aqueous monomethylamine hydrochloride solution was added dropwise at 25°C over 20 minutes. After the dropwise addition, reaction was carried out at 30°C for 5 hours.
  • After the reaction, methanol was distilled off, and 400 g of toluene was added for phase separation. The organic phase obtained by phase separation was returned to the flask, and water was distilled off at 110°C. Toluene that had been distilled off during distillation due to azeotropy with water was separated from the water and returned to the flask. The organic phase was cooled to 25°C, mixed with 60 g (1.0 mol) of acetic acid, and heated to 50°C. After adding 18.9 g (0.5 mol) of sodium borohydride, reaction was carried out at 80°C for 2 hours.
  • After the reaction, the reaction solution was cooled to 25°C, and 290 g of a 12.5 wt.% aqueous sodium hydroxide solution was added thereto for phase separation. The solvent was distilled off from the organic phase thus separated, and the thus-precipitated crystals were filtered. The crystals thus obtained were recrystallized in a mixed solvent of toluene and heptane (weight ratio = 1:3), thereby giving 61.6 g (0.36 mol) of N-monomethyl-3-hydroxy-3-(2-thienyl)propanamine. The yield thereof based on the sodium salt of β-oxo-β-(2-thienyl)propanal was 72.0%.

Claims (7)

  1. A process for producing an N-monoalkyl-3-hydroxy-3-(2-thienyl) propanamine represented by General Formula (2):
    Figure imgb0012
     wherein R is C1-4 alkyl, comprising the step of reducing a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine represented by General Formula (1):
    Figure imgb0013
     wherein R is as defined above.
  2. A process for producing a (Z)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine represented by General Formula (1):
    Figure imgb0014
     wherein R is C1-4 alkyl, comprising the step of reacting an alkali metal salt of β-oxo-β-(2-thienyl) propanal represented by General Formula (3):
    Figure imgb0015
     wherein M is an alkali metal atom, with a monoalkylamine compound represented by General Formula (4):

            H2N-R     (4)

    wherein R is as defined above.
  3. The process according to claim 1, wherein the (Z)-N-monoalkly-3-oxo-3-(2-thienyl) propenamine represented by Formula (1) is produced by the process of claim 2.
  4. The process according to claim 1 or claim 3, wherein the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine is reduced using sodium borohydride or sodium cyanoborohydride.
  5. The process according to any one of claims 1, 3 or 4, wherein the (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine is reduced in the presence of a proton-donating compound.
  6. A (Z)-N-monoalkyl-3-oxo-3-(2-thienyl)propenamine represented by General Formula (1):
    Figure imgb0016
     wherein R is C1-4 alkyl.
  7. The (Z)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine according to claim 6, wherein R in General Formula (1) is methyl.
EP03741391A 2002-08-06 2003-07-15 Process for producing n-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine and intermediate Expired - Lifetime EP1541569B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2002229204 2002-08-06
JP2002229204 2002-08-06
PCT/JP2003/008950 WO2004016603A1 (en) 2002-08-06 2003-07-15 Process for producing n-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine and intermediate

Publications (3)

Publication Number Publication Date
EP1541569A1 EP1541569A1 (en) 2005-06-15
EP1541569A4 EP1541569A4 (en) 2007-05-30
EP1541569B1 true EP1541569B1 (en) 2010-05-12

Family

ID=31884335

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03741391A Expired - Lifetime EP1541569B1 (en) 2002-08-06 2003-07-15 Process for producing n-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine and intermediate

Country Status (8)

Country Link
US (1) US7759501B2 (en)
EP (1) EP1541569B1 (en)
JP (1) JP4493500B2 (en)
CN (1) CN1332958C (en)
CA (1) CA2493776C (en)
DE (1) DE60332544D1 (en)
ES (1) ES2342883T3 (en)
WO (1) WO2004016603A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004346008A (en) * 2003-05-22 2004-12-09 Sumitomo Chem Co Ltd Method for producing n-monoalkyl-3-hydroxy-3-arylpropylamine and intermediate therefor
ES2387061T3 (en) * 2005-08-19 2012-09-12 Sumitomo Seika Chemicals Co., Ltd. (E) -N-monoalkyl-3-oxo-3- (2-thienyl) propenamine and process for its production and (E, Z) -N-monoalkyl-3-oxo-3- (2-thienyl) propenamine and process for its production
EP2044049A2 (en) 2006-07-03 2009-04-08 Ranbaxy Laboratories Limited Process for the preparation of enantiomerically pure salts of n-methyl- 3 -( 1-naph-thaleneoxy)- 3 - (-2-thienyl) propanamine
EP2558455B1 (en) 2010-04-13 2017-08-09 KRKA, D.D., Novo Mesto Synthesis of duloxetine and/or pharmaceutically acceptable salts thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60246348A (en) 1984-05-22 1985-12-06 Tozaburo Kurihara 1-substituted-propylamine and its preparation
IL92508A0 (en) 1988-12-08 1990-08-31 Ciba Geigy Ag Novel alpha-cyano-beta-oxopropionamides
US5543520A (en) * 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives
US5362886A (en) 1993-10-12 1994-11-08 Eli Lilly And Company Asymmetric synthesis
GB9500580D0 (en) * 1995-01-12 1995-03-01 Merck Sharp & Dohme Therapeutic agents
EP1411045B1 (en) * 2002-10-18 2008-01-16 Tohru Yokozawa Process for production of optically active amino alcohols
US6846957B2 (en) * 2002-11-22 2005-01-25 Board Of Regents, The University Of Texas System Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor

Also Published As

Publication number Publication date
JPWO2004016603A1 (en) 2005-12-02
DE60332544D1 (en) 2010-06-24
ES2342883T3 (en) 2010-07-16
EP1541569A1 (en) 2005-06-15
CA2493776A1 (en) 2004-02-26
CA2493776C (en) 2011-05-17
US20050240030A1 (en) 2005-10-27
WO2004016603A1 (en) 2004-02-26
EP1541569A4 (en) 2007-05-30
JP4493500B2 (en) 2010-06-30
CN1671686A (en) 2005-09-21
US7759501B2 (en) 2010-07-20
CN1332958C (en) 2007-08-22

Similar Documents

Publication Publication Date Title
US5043466A (en) Preparation of cyclohexanol derivatives and novel thioamide intermediates
EP1541569B1 (en) Process for producing n-monoalkyl-3-hydroxy-3-(2-thienyl)propanamine and intermediate
JPH02207083A (en) Production of 2-nitroiminoimidazolidines
FI88795C (en) FOERFARANDE FOER FRAMSTAELLNING AV TIENYLETYLAMINER
WO2008010609A1 (en) Process for producing 2-hydroxy-4-(methylthio)butyrate compounds and intermediates thereof
CA2477082A1 (en) Preparation of n-methyl-3-hydroxy- 3-(2-thienyl)propylamine via novel thiophene derivatives containing carbamate groups as intermediates
WO2007045405A1 (en) Process for the preparation of duloxetine
JP5955281B2 (en) (E) -N-monoalkyl-3-oxo-3- (2-thienyl) propenamine and process for producing the same, and (E, Z) -N-monoalkyl-3-oxo-3- (2-thienyl) Propeneamine production method
US6774245B2 (en) 3-Hydroxymethylbenzo[b]thiophene derivatives and process for their preparation
US20090043101A1 (en) Process for production of 5-chloro-2,4-dihydroxypyridine
US7829731B2 (en) Methylhydroxylaminopropanol derivative and its use as intermediate for preparation of 3-methylamino-1-(2-thienyl)propan-1-OL
JP5582682B2 (en) Method for producing substituted 4-alkoxycarbonyl-3-aminothiophenes
JPH01316352A (en) Production of 3-cyano-4-arylpyrrole
KR101147480B1 (en) Method for preparing hydrophilic ionic liquids
WO2004005220A2 (en) Method for asymmetric resolution of a racemic using diprogulic acid and use of said acid as asymmetric resolution agent
EP2128161A1 (en) Process for obtaining 4-hydroxy-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-7,7-dioxide and its enantiomers, and applications thereof
JPH0123468B2 (en)
JPH03157382A (en) Production of 2-(2-thienyl)ethylamine
CZ297555B6 (en) Process for preparing (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
JPS61271291A (en) Production of thienopyridine derivative
HU198196B (en) Process for production of basic tioether and its salts

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050225

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

RBV Designated contracting states (corrected)

Designated state(s): CH DE ES FR GB IT LI

A4 Supplementary search report drawn up and despatched

Effective date: 20070502

17Q First examination report despatched

Effective date: 20080204

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): CH DE ES FR GB IT LI

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 60332544

Country of ref document: DE

Date of ref document: 20100624

Kind code of ref document: P

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2342883

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: SERVOPATENT GMBH

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20110215

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100715

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60332544

Country of ref document: DE

Effective date: 20110214

PGRI Patent reinstated in contracting state [announced from national office to epo]

Ref country code: IT

Effective date: 20110616

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: NEW ADDRESS: WANNERSTRASSE 9/1, 8045 ZUERICH (CH)

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20210727

Year of fee payment: 19

Ref country code: IT

Payment date: 20210727

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20210721

Year of fee payment: 19

Ref country code: CH

Payment date: 20210721

Year of fee payment: 19

Ref country code: GB

Payment date: 20210721

Year of fee payment: 19

Ref country code: ES

Payment date: 20210927

Year of fee payment: 19

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60332544

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20220715

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220731

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220731

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220715

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230201

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20230828

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220716